Mammalian cells express three distinct TGF-beta isoforms, called TGF- beta's 1, 2, and 3. There is already substantial evidence of differential control of expression of these three TGF-beta isoforms both in vitro and in vivo. The purpose of this project is to gain insight into the molecular mechanisms of transcriptional control of TGF-beta expression in mammalian cells by comparative analyses of the promoter regions of the genes for TGF-beta's 1, 2, and 3. The 5' flanking regions of the three genes are distinctly different. The promoters for the TGFbeta 2 and 3 genes contain TATAA boxes just upstream of the start sites, whereas initiation of transcription of the TGF-beta 1 gene is thought to result from a cluster of SP1 binding sites. Selective expression may result from the use of AP-1 sites in the TGF-beta 1 promoter, whereas both the TGF-beta 2 and 3 promoters contain CRE and AP-2 sites which suggest responsiveness to cyclic AMPO. Correlating with the observed high levels of expression of TGF-beta 3 in muscle, it has been found that the TGF-beta 3 promoter is selectively regulated during the differentiation of myoblasts into myotubes through novel sites. Recent studies demonstrate that while several oncogenes such as jun, fos, src, abl, and ras, selectively activate TGF-beta 1 expression through its AP-1 sites, the products of the tumor suppressor gene, Rbl, activates expression of all three TGF-beta promoters through retinoblastoma response elements (RCE) sites. This finding suggests that a general mechanism of growth regulation by RB, a nuclear protein, might involve control of the expression of a secreted peptide which acts to control growth via its interaction with cell-membrane receptors.